1. Field of the Invention
This invention relates to a novel class of steroids which are believed to bind to the progestin receptor and which exhibit potent antiprogestational activity, steroid intermediates which are useful for preparing same and methods for the preparation of steroid intermediates. Such compounds are useful for treatment of fibroids, endometriosis, and certain tumors, in causing cervical ripening prior to delivery, in hormone replacement therapy and in control of fertility and reproduction.
2. Discussion of the Background
Progesterone plays a major role in reproductive health and functioning. Its effects on, for example, the uterus, breast, cervix and hypothalamic-pituitary unit are well established. It also has extra-reproductive activities that are less well studied, such as effects on the brain, the immune system, the vascular endothelial system and on lipid metabolism. Given this wide array of effects, it is apparent that compounds which mimic some of the effects of progesterone (agonists), antagonize these effects (antagonists) or exhibit mixed effects (partial agonists or mixed agonist/antagonist) can be useful in treating a variety of disease states and conditions.
Steroid hormones exert their effects, in-part, by binding to intracellular receptors. Compounds that bind to the appropriate receptors and are antagonists or partial agonists of the estrogenic and androgenic hormones have long been known, but it was not until around 1982 that the discovery of compounds that bind to the progesterone receptor and antagonize the effects of progesterone was announced. Since then, a number of such compounds have been reported in the scientific and patent literature and their effects in vitro, in animals and in humans have been studied. Although compounds such as estrogens and certain enzyme inhibitors can prevent the physiological effects of endogenous progesterone, in this discussion "antiprogestin" is confined to those compounds that bind to the progestin receptor.
Information indicating that antiprogestins would be effective in a number of medical conditions is now available. This information has been summarized in a report from the Institute of Medicine (Donaldson, Molly S.; Dorflinger, L.; Brown, Sarah S.; Benet, Leslie Z., Editors, Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins, Committee on Antiprogestins: Assessing the Science, Institute of Medicine, National Academy Press, 1993). In view of the pivotal role that progesterone plays in reproduction, it is not surprising that antiprogestins could play a part in fertility control, including contraception (long-term and emergency or post-coital), menses induction and medical termination of pregnancy, but there are many other potential uses that have been supported by small clinical or preclinical studies. Among these are the following:
1. Labor and delivery--antiprogestins may be used for cervical ripening prior to labor induction such as at term or when labor must be induced due to fetal death. They may also be used to help induce labor in term or post-term pregnancies.
2. Treatment of uterine leiomyomas (fibroids)--these non-malignant tumors may affect up to 20% of women over 30 years old and are one of the most common reasons for surgery in women during their reproductive years. Hysterectomy, the common treatment for persistent symptoms, of course results in sterility.
3. Treatment of endometriosis--this common (5 to 15% incidence, much larger in infertile women) and often painful condition is now treated with drugs such as danazol or gonadotrophin-releasing hormone analogs that have significant side-effects, or must be dealt with surgically.
4. Hormone replacement therapy, where they may be given to interupt or curtail the activity of progestins.
5. Cancers, particularly breast cancers - the presence of progestin receptors in many breast cancers has suggested the use of antiprogestins in treating metatstatic cancer or in prevention of recurrence or initial development of cancer.
6. Other tumors such as meningiomas--these brain membrane tumors, although non-malignant, result in death of the patient and nonsurgical treatments are lacking.
7. Male contraception--antiprogestins can interfere with sperm viability, although whether this is an antiprogestational effect or not is controversial, as it may relate to the antiglucocorticoid activity of such compounds.
8. Antiestrogenic effects--at least some antiprogestins oppose the action of estrogens in certain tests, but apparently through a mechanism that does not involve classical hormone receptors. This opens a variety of possibilities for their medical use.
9. Antiglucocorticoid effects--this is a common side-effect of antiprogestins, which can be useful in some instances, such as the treatment of Cushing's syndrome, and could play a role in immune disorders, for example. In other instances it is desirable to minimize such effects.
The effects and uses of progesterone agonists have been well documented. In addition, it has been recently shown that certain compounds structurally related to the known antiprogestins have strong agonist activity in certain biological systems (e.g., the classical progestin effects in the estrogen-primed immature rabbit uterus; cf. C. E. Cook et al., Life Sciences, 52, 155-162 (1993)). Such compounds are partial agonists in human cell-derived receptor systems, where they bind to a site distinct from both the progestin and antiprogestin sites (Wagner et al., Proc. Natl. Acad. Sci., 93, 8739-8744 (1996)). Thus the general class of antiprogestins can have many subclasses, which may vary in their clinical profiles.
The earliest antiprogestins, in addition to having an 11.beta.-aryl substituent, were substituted with a 17.beta.-hydroxyl group and various 17.alpha.-substituents. (See for example, Teutsch, Jean G.; Costerousse, Germain; Philibert, Daniel, and Deraedt, Roger. Novel steroids. U.S. Pat. No. 4,386,085. 1983; Philibert, Daniel; Teutsch, Jean G.; Costerousse, Germain, and Deraedt, Roger. 3-Keto-19-nor-.DELTA.-4,9-steroids. U.S. Pat. No. 4,477,445. 1983; Teutsch, Jean G.; Pantin, Germain; Costerousse, Saint-Maurice; Daniel Philibert; La Varenne Saint Hilaire; Roger Deraedt, inventors. Steroid derivatives. Roussel Uclaf, assignee. U.S. Pat. No. 4,447,424. 1984; Cook, C. Edgar; Tallent, C. Ray; Reel, Jerry R., and Wani, Mansukh C. 17.alpha.-(Substituted-methyl)-17.beta.-hydroxy/esterified hydroxy steroids and pharmaceutical compositions containing them. U.S. Pat. Nos. 4,774,236 (1988) and 4,861,763 (1989)). Then it was discovered that a 17.beta.-acetyl, 17.alpha.-acyloxy group in the presence of 11.beta.-aryl could also generate compounds with antiprogestational effects (Cook, C. Edgar; Lee, Y.-W.; Reel, Jerry R.; Wani, Mansukh C., Rector, Douglas. 11.beta.-Substituted Progesterone Analogs. U.S. Pat. Nos. 4,954,490 (1990) and 5,073,548 (1991)), and various permutations of these findings have been made as well. However, introduction of a 16.alpha.-ethyl group or a hydrogen substituent at the 17.alpha.-position in the 17.beta.-acyl series of compounds is reported to lead to agonist or partial agonist activity (C. E. Cook et al., Life Sciences, 52, 155-162 (1993)).
Generally, however, antiprogestational activity has always been associated with the presence of an 11.beta.-aryl substituent on the steroid nucleus, together with a .DELTA..sup.4,9 -3-ketone or .DELTA..sup.4 -3-ketone moiety. A wide latitude has been reported in the substituents on the 11.beta.-aryl moiety associated with antiprogestational activity (cf. Teutsch, G. and Philibert, D. History and perspectives of antiprogestins from the chemist's point of view. Human Reproduction. Jun; 9(Supplement 1):12-31 (1994)). One novel feature of the present invention is the discovery that to achieve a strong and essentially complete antiprogestational response and little or no agonist effect in a classical in vivo measure of progestational response (the McGinty adaptation of the Clauberg test in the estrogen-primed immature female rabbit), the aromatic group at the 11.beta.-position, in the presence of a 17.beta.-acyl-17.alpha.-acyloxy substitution pattern, is best substituted with a basic nitrogen moiety.
The patents of Cook et al. (1989, 1991) referred to above show the use of an acyclic N,N-dimethylamino substituent on the 4-position (para-position) of the 11.beta.-aryl substituent in the presence of the 17.beta.-acetyl, 17.alpha.-acyloxy substitution pattern. Ashby et al. (Ashby J; Paton D; Lefevre P A, Cyclic amines as less mutagenic replacements for dimethyl amino (--NMe.sub.2) substituents on aromatic organic compounds: implications for carcinogenicity and toxicity. Cancer Lett, 1983 17: 263-71 (1983)) find that use of a cyclic amino substituent on certain carcinogenic aryl compounds markedly reduces or eliminates mutagenicity.
Wunerwald et al. DD 290 198 (1991) entitled in part, "11.beta.-aryl substituierten Estra-4,9-dien-3-one-17 (S)-spiro-1'cyclohexan-2'-onen and 11.beta.-arylsubstituierten Estra-4,9-dien-3-one-17 (S)-spiro-1'cyclohexan-2'-olen sowie deren derivate" illustrates steroid compounds bearing C.sub.17 spirocyclic ketone and alcohol substitution.
Rohde et al. U.S. Pat. No. 4,609,651 report 11.beta.-Arylestradienes, their production and pharmaceutical preparations containing same. These compounds are 17.beta.-hydroxy- 17.alpha.-alkenyl substituted.
Kim et al. PCT WO96/30390 (1996) report a method for preparing 17.alpha.-acetoxy-11.beta.-(4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-d iene-3,20-dione, intermediates useful in the method and method for the preparation of such intermediates. Both the 11.beta.-4-N,N-dimethylaminophenyl and the .alpha.-acetoxy groups are indicated as essential. Neither nitrogen heterocycles nor 17.alpha.-carbonyloxy groups are suggested.
Kim et al. PCT WO97/4145 reports 21-substituted progesterone derivatives bearing a 11.beta.-substituted phenyl group but no heterocyclic substitutions.
In spite of the clinical promise of antiprogestins, as of Jan. 1, 1998, there were no antiprogestin drugs marketed in the United States or many other countries. Only one antiprogestin drug is approved and available for clinical use anywhere in the world and that drug, mifepristone, is mainly used for medical termination of pregnancy. A number of factors are the cause of this situation, but certainly a need exists for new antiprogestational drugs that can be used for the conditions described above.
Accordingly there remains a need for antiprogestin compounds which exhibit higher specificity.